Synthesis and cycloaddition reactions of sulfur-substituted quinolizidine dienes

Article abstract of DOI:10.1016/j.tet.2011.04.106

Synthesis of sulfur-substituted quinolizidine dienes via ring-closing enyne metathesis (RCEYM) of the corresponding enynes has been achieved. The cycloaddition reactions of these dienes with electron-deficient dienophiles give tricyclic and tetracyclic ni

Full text of DOI:10.1016/j.tet.2011.04.106

Tetrahedron 67 (2011) 4505e4513
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Synthesis and cycloaddition reactions of sulfur-substituted quinolizidine dienes
*
Shang-Shing P. Chou , Chien-Wen Huang, Chih-Chun Chang
Department of Chemistry, Fu Jen Catholic University, New Taipei City 24205, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 March 2011
Received in revised form 20 April 2011
Accepted 29 April 2011
Available online 6 May 2011
Synthesis of sulfur-substituted quinolizidine dienes via ring-closing enyne metathesis (RCEYM) of the
corresponding enynes has been achieved. The cycloaddition reactions of these dienes with electron-
deficient dienophiles give tricyclic and tetracyclic nitrogen-containing products.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ring-closing enyne metathesis (RCEYM)
Quinolizidine dienes
Cycloaddition reactions
Nitrogen heterocycles
1. Introduction
respectively. The yield of 2b was considerably lower than that of 2a,
probably due to steric hindrance of the electrophile. Heating the
Enyne metathesis is a bond reorganization of an alkene and an
alkyne to produce
conjugated diene.1 If carried out in-
3-sulfolenes 2 with p-toluenesulfonyl isocyanate (PTSI) in toluene
gave the aza-DielseAlder reaction products,4 which were directly
treated with triethylamine in ethyl acetate to provide the conju-
gated dihydropyridones 3a and 3b. Cleavage of the N-tosyl group by
Bu3SnH/AIBN8 afforded the secondary amides 4a and 4b in good
yield. Treatment of amides 4 with BuLi in THF at ꢀ78 ꢁC in the
presence of HMPA followed by reaction with allyl bromide or
3-bromo-2-methylpropene gave the N-allylated products 5aec.
a
tramolecularly, this reaction is often referred to as ring-closing
enyne metathesis (RCEYM) because an additional ring is formed
during this process. RCEYM is a powerful tool for the synthesis of
carbocycles2 and various heterocycles3 bearing a conjugated diene
moiety, which can further undergo DielseAlder reactions with
dienophiles to form more complex structures.
We have previously developed a new aza-DielseAlder reaction
of thio-substituted 3-sulfolenes with p-toluenesulfonyl isocyanate
(PTSI) to synthesize sulfur-substituted piperidine derivatives,4 and
have used this method to prepare some indolizidines and quinoli-
zidines,5 which often show interesting biological activities.6 We
now report our studies using this method in combination with the
RCEYM strategy to make sulfur-substituted quinolizidine dienes,
and our results of their cycloaddition reactions with electron-
deficient dienophiles to provide a rapid synthesis of tricyclic and
tetracyclic nitrogen-containing compounds.
SPh
SPh
1) Ts-N=C=O, NaHCO3
HQ, Tol, 110 o
1) BuLi, THF, HMPA, ¡Ð78oC
S
C
O2
S
2) 1-bromo-2-butyne or 3-bromo-
1-(trimethylsilyl)propyne
2) Et3N, EtOAc, rt
O2
R
2a, R = Me (72%)
1
2b, R = TMS (37%)
SPh
SPh
SPh
1) BuLi, THF
HMPA, ¡Ð78 o
C
Bu3SnH, AIBN
N
O
N
Ts
O
Tol, reflux
N
H
O
2) allyl bromide or
3-bromo-2-
R'
methylpropene
2. Results and discussion
R
R
R
5a, R = Me, R' = H (83%)
5b, R = Me, R' = Me (87%)
5c, R = TMS, R' = H(82%)
4a, R = Me (80%)
4b, R = TMS (90%)
3a, R = Me (63%)
3b, R = TMS (59%)
Preparation of the enyne precursors 5 for the RCEYM is shown in
Scheme 1. Treatment of 3-(phenylthio)-3-sulfolene (1)7 with BuLi
in THF at ꢀ78 ꢁC in the presence of hexamethylphosphoric amide
(HMPA) followed by reaction with1-bromo-2-butyne or 3-bromo-
1-(trimethylsilyl)propyne gave the alkylated products 2a and 2b,
Scheme 1.
The results of ring-closing enyne metathesis (RCEYM) of com-
pounds 5 under various conditions are shown in Table 1. Reaction of
compound 5a with Grubbs’ I catalyst (G1) in CH2Cl2 at room tem-
perature gave the diene 6a in high yield (entry 1). However, the
* Corresponding author. Fax: þ886 2 29023209; e-mail address: chem1004@
mails.fju.edu.tw (S.-S.P. Chou).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.106

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S.-S.P. Chou et al. / Tetrahedron 67 (2011) 4505e4513
Table 1
followed by reaction with 2-bromopropyne or 1-bromo-2-butyne
RCEYM reaction of compounds 5 with Grubbs’ catalysts
gave the N-alkylated products 9a and 9b. RCEYM of compounds 9a
and 9b with G1 in CH2Cl2 at room temperature afforded the cor-
responding dienes 10a and 10b in fair to good yield.
SPh
SPh
SPh
N
N
O
R'
The reaction of diene 6a with tetracyanoethene (TCNE) was
carried out in toluene in a sealed tube at 160 ꢁC to give a mixture of
two cycloaddition products 11a and 11b, which were separated by
column chromatography. The X-ray crystal structure of compound
11a (Fig.1)9 shows that the two hydrogens at the ring junction (H-10
and H-14) are trans to each other, and that the quinolizidine ring has
a cis conformation. The major product 11b is an oil; its structure was
established by the NOESY spectrum (see the Supplementary data),
which shows cross signals between the H-10 and H-14 (Fig. 2). On
the other hand, compound 11a does not show cross signals between
the H-10 and H-14 in its NOESY spectrum. Compounds 11a and 11b
are facial stereoisomers. The major isomer 11b results from the ap-
proach of TCNE opposite to the H-10 of diene 6a. This mode of re-
action is different from that with N-phenyl- or N-methylmaleimide
(vide infra), which prefers endo addition. For the reactionwith TCNE,
there is no distinction between endo and exo addition. We speculate
that the cyano group of TCNE may have some dipole or orbital in-
teraction with the carbonyl group of the diene 6a.
N
O
(Table 1)
O
R'
R
R'
R
R
5a, R = Me, R' = H
5b, R = Me, R' = Me
5c, R = TMS, R' = H
6a, R = Me, R' = H
6b, R = H, R' = H
7a, R = Me, R' = Me
7b, R = TMS, R' = H
Entry
Reactant
Catalyst
Conditions
Product (%)
1
2
3
4
5
6
7
8
9
5a
5b
5b
5b
5b
5b
5c
5c
5c
G1 (10 mol %)
G1 (10 mol %)
G1 (10 mol %)
G1 (10 mol %)
G2 (5 mol %)
G2 (5 mol %)
G1 (10 mol %)
G1 (10 mol %)
G2 (5 mol %)
CH2Cl2, rt, 18 h
CH2Cl2, rt, 18 h
CH2Cl2, reflux, 18 h
Tol, 85 ꢁC, 25 h
CH2Cl2, reflux, 24 h
Tol, reflux, 21 h
CH2Cl2, rt, 18 h
CH2Cl2, reflux, 9 h
CH2Cl2, reflux, 22 h
6a (80)
NRa
7a (21)b
7a (11)c
NRa
NRa
NRa
6b (66)
7b (14)d
a
No reaction was observed.
b
c
Compound 5b was recovered in 67%.
Compound 5b was recovered in 63%.
Compound 5c was recovered in 62%.
d
reaction of compound 5b with G1 in CH2Cl2 at room temperature
(entry 2) gave only the recovered starting material. The lower re-
activity of compound 5b than 5a is probably due to the steric effect.
Heating compound 5b with G1 in refluxing CH2Cl2 (entry 3) or in
toluene at 85 ꢁC (entry 4) gave the alkene-isomerized product 7a in
low yield, together with some unreacted starting material. If
compound 5b was treated with G2 in refluxing CH2Cl2 (entry 5) or
in refluxing toluene (entry 6), only the unreacted starting material
was obtained. The reaction of compound 5c with G1 in CH2Cl2
(entry 7) did not proceed at room temperature, but yielded the
diene 6b in good yield in refluxing CH2Cl2 (entry 8). It should be
noted that compound 6b has lost the TMS group in compound 5c
during the RCEYM. The reaction of compound 5c with G2 in
refluxing CH2Cl2 (entry 9) gave the alkene-isomerized product 7b
in 14% besides the recovered starting material.
PCy
Ru
PCy3
Mes
N
Cl
Cl
N
Mes
Ph
3 Ph
Cl
Cl
Ru
PCy3
Fig. 1. X-ray crystal structure of compound 11a.
G1
G2
We have also developed another route for constructing the
sulfur-substituted quinolizidine dienes 10 (Scheme 2). Treatment of
compound 85a with sodium hydride in THF at room temperature
SPh
SPh
1) NaH, THF, rt, 30 min
Fig. 2. NOESY correlations of compound 11b.
N
O
2) 2-bromopropyne or
1-bromo-2-butyne
reflux, 2 h
N
H
O
The reaction of diene 6a with dimethyl acetylenedicarboxylate
(DMAD) in toluene at 80 ꢁC yielded a mixture of cycloaddition
products 12a and 12b in about equal amounts. These two com-
pounds were separated by column chromatography. The X-ray
crystal structure of compound 12a (Fig. 3)9 shows that the two
hydrogen atoms at the ring junction (H-10 and H-14) are trans to
each other, and that the quinolizidine ring has the trans confor-
mation. The other product 12b is a liquid, whose structure was
established by its NOESY spectrum (see the Supplementary data),
which shows cross signals between the H-10 and H-14. As com-
pared to the reaction of diene 6a with TCNE, the reaction of diene
R
8
9a, R = H (50%)
9b, R = Me (62%)
SPh
G1 (10 mol%)
N
O
CH2Cl2, rt, 24 h
10a, R = H (62%)
10b, R = Me (82%)
R
Scheme 2.

S.-S.P. Chou et al. / Tetrahedron 67 (2011) 4505e4513
4507
Fig. 5. NOESY correlations of compound 14b.
It should be noted that both compounds 14a/14b and 15a/15b
were the endo addition products, probably favored by secondary
orbital interactions. Furthermore, the major products 14a and 15a
resulted from approach of the maleimides from the same side as
the H6a of diene 6a. A molecular model for the endo addition of
maleimides from the opposite side of H6a of diene 6a shows a se-
vere steric repulsion with the H-60 of diene 6a (Fig. 6). Also, the
approach of the dienophiles from the less hindered convex face
seems to be more favorable than from the concave face.
Fig. 3. X-ray crystal structure of compound 12a.
6a with DMAD showed no facial selectivity. This is probably be-
cause DMAD is a linear molecule and has less steric hindrance. We
also found that compound 12b could be oxidized by 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ) to the aromatic compound
13 in good yield. It should be noted that compound 12b was con-
siderably less stable than compound 12a; the former was partially
oxidized to compound 13 in the air.
Fig. 6. Steric repulsion of maleimides with diene 6a.
Reactions of diene 6a with N-phenylmaleimide and N-methyl-
maleimide in toluene in a sealed tube at 160 ꢁC yielded a mixture of
steroid-like skeleton products 14a/14b and 15a/15b, respectively.
These products were separated by column chromatography as vis-
cous liquids. The structures of these compounds were determined by
NMR spectroscopic methods (see the Supplementary data). The
NOESY spectrum of compound 14a shows cross signals between H-
6a and H-12, and between H-120, H-12a and H-12b (Fig. 4). On the
other hand, the NOESY spectrum of compound 14b has cross signals
betweenH-60 andH-120, andbetweenH-12, H-12aandH-12b(Fig. 5).
Reactions of dienes 10a and 10b with N-phenylmaleimide and
N-methylmaleimide proceeded much faster than those of diene 6a,
and were carried out by heating in toluene at 80 ꢁC for 13 h to give
a mixture of endo products 16ae19a and exo products 16be19b.
The ratios of these isomers were estimated from the 1H NMR in-
tegrations of the H-6 doublets. The stereochemistry proposed for
compound 16a was based on a literature report for a related case,
which was confirmed by X-ray diffraction.3d The structure of
compound 16b was determined by NOESY spectra (see the
Supplementary data) and comparison with the NMR spectrum of
a similar compound reported in the literature.3d The NOESY cor-
relations of the major products 17a (Fig. 7) and 18a (Fig. 8) show
that these are the endo addition products with the N-phenyl- or
N-methylmaleimide approaching from the less hindered side of the
dienes 10a and 10b, i.e., the same side as the H-10a.
The reaction of diene 10b with 4-(phenylsulfonyl)-1-tosyl-
5,6-dihydro-2-pyridone (20)4b in toluene in a sealed tube at 160 ꢁC
yielded the cycloaddition product 21. However, diene 10a did not
react under this condition; heating at 180 ꢁC resulted only in the
decomposition of diene 10a. The structure of the exo addition
product 21 was confirmed by X-ray crystallography (Fig. 9),9 which
also shows that the quinolizidine ring has a cis conformation. We
propose that the dienophile 20 approaches diene 10b from the less
hindered side (the same side as the H-10a) to give product 21. The
steric bulkiness of the phenylsulfonyl group of dienophile 20 would
disfavor the endo addition. We have previously shown that com-
pound 20 can react with 1-methoxy-3-trimethylsilyloxy-1,3-buta-
diene, 2,3-dimethylbutadie-ne, or cyclopentadiene at 140e160 ꢁC.10
Fig. 4. NOESY correlations of compound 14a.

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S.-S.P. Chou et al. / Tetrahedron 67 (2011) 4505e4513
respectively. We propose that PTSI first undergoes a [2þ2] cyclo-
addition reaction with the C]O of the dienes 10 followed by
elimination of CO2 to give the C]N products 22.10 The X-ray crystal
structure of compound 22b (Fig.10)9 shows that the C]N has the E-
configuration, and the quinolizidine ring has a cis conformation.
Fig. 7. NOESY correlations of compound 17a.
Fig. 10. X-ray crystal structure of compound 22b.
Similar reaction of diene 6a with PTSI also produced the imine
product 23. The similarity of its NMR spectral data with those of
compound 22b led us to propose that compound 23 also has the
E-configuration of the C]N bond. Further reaction of compound 23
with N-phenylmaleimide in toluene in a sealed tube at 160 ꢁC gave
a mixture of cycloaddition products 24a and 24b. The stereo-
selectivity of this reaction was similar to that obtained for diene 6a.
Fig. 8. NOESY correlations of compound 18a.
3. Conclusions
In summary, we have developed two facile routes (Schemes 1
and 2) to prepare the enynes 5 and 9, which could be converted,
respectively, to the quinolizidine dienes 6 and 10 via ring-closing
enyne metathesis (RCEYM). We have also studied the cycloaddi-
tion reactions of dienes 6a, 10a, and 10b with various
electron-deficient dienophiles to give tricyclic and tetracyclic
nitrogen-containing products, which could have some biological
activities. The stereochemistry of these reactions is affected by the
structures of the dienes and dienophiles.
Fig. 9. X-ray crystal structure of compound 21.
It is interesting to note that cyclopentadiene reacts with compound
20 to give only the endo addition product. Apparently, diene 10b is
much more sterically hindered than cyclopentadiene.
The reaction of dienes 10a and 10b with p-toluenesulfonyl iso-
cyanate (PTSI) did not undergo the expected DielseAlder reaction.
Instead, the imine products 22a and 22b were obtained,

S.-S.P. Chou et al. / Tetrahedron 67 (2011) 4505e4513
4509
4. Experimental section
4.1. General
31.9, 23.3, 21.4, 3.4; FAB-MS m/z 412 (MþþH, 100); FAB-HRMS calcd
for C22H21NO3S2 411.0963, found 411.0969.
4.1.4. 4-(Phenylthio)-1-tosyl-6-(3-(trimethylsilyl)prop-2-ynyl)-
5,6-dihydropyridin-2(1H)-one (3b). Using a similar condition as for
compound 3a, product 3b (91 mg, 59%) was obtained as a white
solid: mp 114e116 ꢁC (recryst from EA/hexanes); IR (film) 3058,
Melting points were determined with a SMP3 melting appara-
tus. Infrared spectra were recorded with a Perkin Elmer 100 series
FTIR spectrometer. 1H and 13C NMR spectra were recorded on
a Bruker Avance 300 or 600 spectrometer operating at 300 or 600,
and at 75 or 150 MHz, respectively, unless specified otherwise.
2240, 1678, 1597, 1374 cmꢀ1 1H NMR (CDCl3)
; d 7.92 (2H, d,
J¼8.0 Hz), 7.48e7.37 (5H, m), 7.27 (2H, d, J¼8.0 Hz), 5.18 (1H, s),
Chemical shifts (d) are reported in parts per million (ppm) and the
4.97e4.91 (1H, m), 2.93 (2H, d, J¼3.3 Hz), 2.67 (2H, d, J¼7.5 Hz),
coupling constants (J) are given in hertz. High resolution mass
spectra (HRMS) were measured with a mass spectrometer Fin-
nigan/Thermo Quest MAT 95XL. X-ray crystal structures were
obtained with an EnrafeNonius FR-590 diffractometer (CAD4,
Kappa CCD). Elemental analyses were carried out with Heraeus
Vario III-NCSH, Heraeus CHNeOeS-Rapid Analyzer or Elementar
Vario EL III. Flash column chromatographic purifications were
performed using Merck 60H silica gel.
2.39 (3H, s), 0.18 (9H, s); 13C NMR (CDCl3)
d 160.4, 157.6,144.7, 136.5,
135.3, 130.5, 130.0, 129.3, 129.0, 127.5, 113.5, 101.4, 89.1, 53.4, 32.2,
24.5, 21.6, -0.1; FAB-MS m/z 470 (MþþH, 90); FAB-HRMS calcd for
C24H27NO3S2Si 469.1202, found 469.1195.
4.1.5. 6-(But-2-ynyl)-4-(phenylthio)-5,6-dihydropyridin-2(1H)-one
(4a). To a refluxing solution of compound 3a (360 mg, 0.88 mmol)
in degassed toluene (15 mL) was added dropwise a solution of
Bu3SnH (0.28 mL, 1.06 mmol) and AIBN (86 mg, 0.52 mmol) in
toluene (5 mL). The reaction mixture was refluxed for another 2 h.
The solvent was then evaporated under vacuum, and the crude
product was purified by flash chromatography using ethyl acetate/
hexanes (1:1) containing 5% Et3N as eluent to give compound 4a
(180 mg, 80%) as a white solid: mp 136e137 ꢁC (recryst from
4.1.1. 2-(But-2-ynyl)-4-(phenylthio)-3-sulfolene (2a). To a solution
of compound 1 (565 mg, 2.50 mmol) in THF (8 mL) and HMPA
(1.74 mL, 10 mmol) under nitrogen at ꢀ78 ꢁC was added dropwise
a solution of BuLi in hexane (2.5 M, 1.2 mL, 3.00 mmol). After stir-
ring at ꢀ78 ꢁC for 30 min, 1-bromo-2-butyne (0.9 mL, 10.00 mmol)
was added in one portion. The mixture was slowly warmed to
ꢀ40 ꢁC, and was maintained at this temperature for 3 h before it
was poured into a saturated ammonium chloride solution. The
aqueous solution was extracted three times with ethyl acetate, and
the combined organic layers were dried (MgSO4) and evaporated
under vacuum. The crude product was purified by flash chroma-
tography using ethyl acetate/hexanes (1:8) as eluent to give com-
pound 2a (500 mg, 72%) as a yellow oil: IR (film) 3060, 2227, 1583,
CH2Cl2/hexanes); IR (film) 3053, 1656, 1590, 1265 cmꢀ1
;
1H NMR
(CDCl3) 7.52e7.38 (5H, m), 5.77 (1H, br s), 5.28 (1H, s), 3.75e3.65
d
(1H, m), 2.51e2.43 (2H, m), 2.42e2.30 (2H, m), 1.79 (3H, t,
J¼2.4 Hz); 13C NMR (CDCl3)
d 165.7, 154.6, 135.4, 130.0, 129.9, 128.1,
114.2, 79.5, 73.8, 50.2, 34.0, 25.2, 3.5; EI-MS m/z 257 (Mþ, 2); EI-
HRMS calcd for C15H15NOS 257.0874, found 257.0870. Anal. Calcd
for C15H15NOS: C, 70.01; H, 5.87; N, 5.44. Found: C, 70.03; H, 5.93; N,
5.56.
1313, 1123 cmꢀ1 1H NMR (CDCl3)
; d 7.47e7.36 (5H, m), 5.92e5.90
(1H, m), 3.95e3.90 (1H, m), 3.72 (2H, t, J¼1.5 Hz), 2.79e2.69 (1H,
4.1.6. 4-(Phenylthio)-6-(3-(trimethylsilyl)prop-2-ynyl)-5,6-dihy-
dropyridin-2(1H)-one (4b). Using a similar condition as for com-
pound 4a, product 4b (500 mg, 90%) was isolated as a white solid:
mp 164e166 ꢁC (recryst from CH2Cl2/hexanes); IR (film) 3180, 3053,
m), 2.60e2.51 (1H, m), 1.78 (3H, t, J¼2.4 Hz); 13C NMR (CDCl3)
d
133.3,132.5,129.7,129.6,129.1,124.8, 79.1, 73.1, 65.7, 57.7,19.5, 3.5;
FAB-MS m/z 279 (MþþH, 4); FAB-HRMS calcd for C14H14O2S2
278.0435, found 278.0436.
2181, 1662, 1244, 1047 cmꢀ1; 1H NMR (CDCl3)
d
7.50e7.36 (5H, m),
6.18 (1H, br s), 5.27 (1H, s), 3.75e3.69 (1H, m), 2.55 (1H, dd, J¼16.5,
5.4 Hz), 2.49e2.39 (3H, m), 0.13 (9H, s); 13C NMR (CDCl3)
165.6,
4.1.2. 4-(Phenylthio)-2-(3-(trimethylsilyl)prop-2-ynyl)-3-sulfolene
(2b). Using a similar condition as for compound 2a except for
warming the reaction mixture to ꢀ60 ꢁC for 2.5 h, compound 2b
was isolated as a yellow oil (124 mg, 37%): IR (film) 3058, 2179,
d
154.3, 135.3, 130.0, 129.8, 128.1, 114.3, 101.3, 88.4, 49.8, 33.6, 26.1,
ꢀ0.1; EI-MS m/z 316 (Mþþ1, 1); EI-HRMS calcd for C17H21NOSSi
315.1113, found 315.1119.
1583, 1316, 1126 cmꢀ1 1H NMR (CDCl3)
; d 7.48e7.37 (5H, m), 5.77
(1H, dt, J¼3.0, 1.5 Hz), 3.94e3.89 (1H, m), 3.73 (2H, t, J¼1.5 Hz),
4.1.7. 1-Allyl-6-(but-2-ynyl)-4-(phenylthio)-5,6-dihydropyridin-
2(1H)-one (5a). To a solution of compound 4a (300 mg, 1.17 mmol)
in THF (7 mL) and HMPA (0.81 mL, 4.68 mmol) under nitrogen at
ꢀ78 ꢁC was added dropwise a solution of BuLi in hexane (2.5 M,
1.2 mL, 3.00 mmol). After stirring at ꢀ78 ꢁC for 30 min, allyl bro-
mide (0.4 mL, 4.68 mmol) was added in one portion. The mixture
was slowly warmed to room temperature, and was stirred for
another 2 h before it was poured into a saturated ammonium
chloride solution. The aqueous solution was extracted three times
with ethyl acetate, and the combined organic layers were dried
(MgSO4) and evaporated under vacuum. The crude product was
purified by flash chromatography using ethyl acetate/hexanes
(1:5) as eluent to give compound 5a (288 mg, 83%) as a white
solid: mp 89e90 ꢁC (recryst from EA/hexanes); IR (film) 3053,
2.78 (1H, dd, J¼17.1, 5.4 Hz), 2.62 (1H, dd, J¼17.1, 8.1 Hz), 0.14
(9H, t, J¼3.3 Hz); 13C NMR (CDCl3)
d 133.5, 133.0, 129.6, 129.1,
129.0, 122.8, 100.4, 88.2, 64.9, 57.4, 20.4, ꢀ0.2; FAB-MS m/z 337
(MþþH, 6); FAB-HRMS calcd for C16H20O2S2Si 336.0674, found
336.0675.
4.1.3. 6-(But-2-ynyl)-4-(phenylthio)-1-tosyl-5,6-dihydropyridin-
2(1H)-one (3a). A mixture of compound 2a (568 mg, 2.04 mmol),
NaHCO3 (171 mg, 2.04 mmol), hydroquinone (11.2 mg, 0.10 mmol),
and PTSI (1.25 mL, 8.16 mmol) in toluene (10 mL) was heated at
reflux under nitrogen for 6 h. After cooling in an ice bath, 5% aq
NaOH was slowly added to decompose the excess PTSI. The solvent
was removed under vacuum, and the residue was purified by flash
chromatography using ethyl acetate/hexanes (1:6) containing 5%
Et3N as eluent to give compound 3a (533 mg, 63%) as a white solid:
mp 154e155 ꢁC (recryst from EA/hexanes); IR (film) 3053, 2232,
1639, 1595, 1455, 1253 cmꢀ1; 1H NMR (CDCl3)
d 7.53e7.39 (5H, m),
5.78 (1H, dddd, J¼17.1, 10.2, 6.6, 4.8 Hz), 5.38 (1H, d, J¼2.1 Hz),
5.22e5.15 (2H, m), 4.59 (1H, ddt, J¼15.6, 4.8, 1.5 Hz), 3.63e3.56
(1H, m), 3.46 (1H, dd, J¼15.6, 6.6 Hz), 2.79 (1H, ddd, J¼17.1, 6.3,
2.1 Hz), 2.65 (1H, dd, J¼17.1, 2.1 Hz), 2.46e2.41 (2H, m), 1.79e1.76
1660, 1594, 1344, 1164 cmꢀ1 1H NMR (CDCl3)
; d 7.92 (2H, d,
J¼8.1 Hz), 7.46e7.27 (5H, m), 7.25 (2H, d, J¼8.1 Hz), 5.20 (1H, s),
4.93e4.87 (1H, m), 2.90 (2H, d, J¼3.3 Hz), 2.59e2.55 (2H, m), 2.37
(3H, m); 13C NMR (CDCl3)
d 162.1, 150.7, 135.1, 133.6, 129.6, 129.5,
(3H, s), 1.77 (3H, t, J¼2.4 Hz); 13C NMR (CDCl3)
d
160.2, 157.5, 144.5,
128.4, 116.9, 115.0, 78.3, 74.9, 53.9, 46.8, 31.7, 21.3, 3.3; EI-MS m/z
136.4, 135.2, 130.2, 129.8, 129.1, 128.7, 127.3, 113.2, 79.4, 74.1, 53.7,
297 (Mþ, 14); EI-HRMS calcd for C18H19NOS 297.1187, found

4510
S.-S.P. Chou et al. / Tetrahedron 67 (2011) 4505e4513
297.1184. Anal. Calcd for C18H19NOS: C, 72.69; H, 6.44; N, 4.71.
Found: C, 72.68; H, 6.31; N, 4.95.
13C NMR (CDCl3)
d 162.8, 151.8, 135.5, 133.1, 130.0, 129.9, 128.5,
122.2, 115.2, 78.6, 75.3, 57.6, 31.6, 22.5, 21.6, 18.2, 3.6; EI-MS m/z 311
(Mþ, 3); EI-HRMS calcd for C19H21NOS 311.1344, found 311.1347.
4.1.8. 6-(But-2-ynyl)-1-(2-methylallyl)-4-(phenylthio)-5,6-dihy-
dropyridin-2(1H)-one (5b). Using a similar condition as for com-
pound 5a, product 5b (126 mg, 87%) was obtained as a yellow oil: IR
4.1.13. (E)-4-(Phenylthio)-1-(prop-1-enyl)-6-(3-(trimethylsilyl)prop-
2-ynyl)-5,6-dihydropyridin-2(1H)-one (7b). A mixture of compound
5c (218 mg, 0.61 mmol) and G2 (30 mg, 0.03 mmol) in CH2Cl2
(6 mL) was refluxed under nitrogen for 22 h. The solvent was then
evaporated under vacuum, and the residue was purified by flash
chromatography using ethyl acetate/hexanes (1:5) as eluent to give
compound 7b (31 mg, 14%) as a yellow oil: IR (film) 3053, 2176,
(film) 3068, 1642, 1596, 1454, 1440, 1248 cmꢀ1 1H NMR (CDCl3)
;
d
7.54e7.38 (5H, m), 5.39 (1H, d, J¼2.4 Hz), 4.89e4.85 (2H, m), 4.65
(1H, d, J¼15.6 Hz), 3.59e3.52 (1H, m), 3.29 (1H, d, J¼15.6 Hz), 2.79
(1H, ddd, J¼17.1, 6.3, 1.8 Hz), 2.65 (1H, dd, J¼17.1, 1.8 Hz), 2.51e2.35
(2H, m), 1.77 (3H, t, J¼2.4 Hz), 1.70 (3H, s); 13C NMR (CDCl3)
d 162.2,
150.8, 140.9, 135.1, 129.6, 129.5, 128.2, 114.7, 112.2, 78.2, 75.0, 53.4,
49.4, 31.5, 20.8, 19.8, 3.3; FAB-MS m/z 312 (MþþH, 100); FAB-HRMS
calcd for C19H21NOS 311.1344, found 311.1335.
1651, 1596, 1417, 1249 cmꢀ1 1H NMR (CDCl3)
; d 7.54e7.39 (5H, m),
7.10 (1H, dq, J¼14.7, 1.8 Hz), 5.39 (1H, d, J¼2.1 Hz), 5.06 (1H, dq,
J¼14.7, 6.6 Hz), 4.09e4.02 (1H, m), 2.86 (1H, ddd, J¼17.1, 6.3,
2.1 Hz), 2.75 (1H, dd, J¼17.1, 2.1 Hz), 2.54e2.51 (2H, m), 1.74 (3H, dd,
4.1.9. 1-Allyl-4-(phenylthio)-6-(3-(trimethylsilyl)prop-2-ynyl)-
5,6-dihydropyridin-2(1H)-one (5c). Using a similar condition as for
compound 5a, product 5c (83 mg, 82%) was obtained as a yellow
oil: IR (film): IR (film) 3053, 2175, 1642, 1454, 1250 cmꢀ1; 1H NMR
J¼6.6, 1.8 Hz), 0.18 (9H, t, J¼3.3 Hz); 13C NMR (CDCl3)
d 159.9, 152.5,
135.4, 130.1, 129.9, 128.2, 125.0, 114.6, 105.3, 102.6, 87.9, 51.9, 30.9,
21.6, 15.5, 0.1; EI-MS m/z 355 (Mþ, 11); EI-HRMS calcd for
C20H25NOSSi 355.1426, found 355.1421.
(CDCl3)
d
7.53e7.39 (5H, m), 5.78 (1H, dddd, J¼17.1, 10.2, 6.9,
4.8 Hz), 5.39 (1H, d, J¼2.4 Hz), 5.24e5.16 (2H, m), 4.61 (1H, ddt,
J¼15.6, 4.8, 1.8 Hz), 3.70e3.63 (1H, m), 3.49 (1H, dd, J¼15.6, 6.9 Hz),
2.81 (1H, ddd, J¼17.1, 6.3, 2.4 Hz), 2.61 (1H, dd, J¼17.1, 1.8 Hz), 2.54
4.1.14. 6-Allyl-4-(phenylthio)-1-propargyl-1,2,5,6-tetrahydropyridin-
2-one (9a). A mixture of compound 8 (200 mg, 0.82 mmol) and
NaH (60%, 58.7 mg, 1.48 mmol) in THF (4 mL) was stirred at room
temperature for 45 min. Propargyl bromide (0.29 mL, 3.28 mmol)
was then added, and the reaction mixture was refluxed for 2 h. The
solvent was removed under vacuum, and the crude product was
purified by flash chromatography using ethyl acetate/hexanes (1:5)
as eluent to give compound 9a (114 mg, 50% yield) as a yellow oil:
(1H, s), 2.52 (1H, s), 0.16 (9H, s); 13C NMR (CDCl3)
d 162.3, 151.0,
135.3, 133.8, 130.0, 129.9, 128.5, 117.3, 115.2, 102.8, 87.9, 53.9, 47.2,
32.2, 22.7, 0.0; EI-MS m/z 355 (Mþ, 2); EI-HRMS calcd for
C20H25NOSSi 355.1426, found 355.1425.
4.1.10. 2-(Phenylthio)-8-(prop-1-en-2-yl)-1,6,9,9a-tetrahy-
droquinolizin-4-one (6a). A mixture of compound 5a (86 mg,
0.29 mmol) and G1 (24.0 mg, 0.029 mmol) in CH2Cl2 (5 mL) was
stirred under nitrogen at room temperature for 16 h. The solvent
was then evaporated under vacuum, and the residue was purified
by flash chromatography using ethyl acetate/hexanes (1:5) as elu-
ent to give compound 6a (69 mg, 80%) as a yellow oil: IR (film)
IR (film) 3291, 3062, 2118, 1642, 1590, 1454, 1251 cmꢀ1
;
1H NMR
(CDCl3) 7.49e7.39 (5H, m), 5.75e5.68 (1H, m), 5.34 (1H, d,
d
J¼2.1 Hz), 5.19e5.17 (1H, m), 5.13 (1H, s), 4.71 (1H, dd, J¼2.4,
17.7 Hz), 3.88e3.78 (2H, m), 2.83 (1H, ddd, J¼2.1, 6.3, 16.8 Hz),
2.48e2.34 (3H, m), 2.23 (1H, t, J¼2.7 Hz); 13C NMR (CDCl3)
d 162.5,
152.0, 135.4, 133.7, 130.0, 129.8, 128.4, 119.5, 114.6, 79.3, 72.1, 54.2,
35.7, 33.8, 32.0; FAB-MS m/z 284 (MþþH, 100); FAB-HRMS calcd for
C17H18NSO 284.1109, found 284.1113.
3054, 1634, 1596, 1424, 1265 cmꢀ1 1H NMR (CDCl3)
; d 7.53e7.40
(5H, m), 5.82 (1H, br s), 5.34 (1H, s), 4.96e4.94 (2H, m), 4.66 (1H, br
d, J¼19.8 Hz), 3.79e3.69 (2H, m), 2.83 (1H, dd, J¼17.1, 6.6 Hz),
4.1.15. 6-Allyl-1-(2-butynyl)-4-(phenylthio)-1,2,5,6-tetrahydropyr-
idin-2-one (9b). Using a similar condition as for compound 9a,
product 9b (380 mg, 62% yield) was obtained as a yellow oil: IR
2.50e2.38 (3H, m), 1.90 (3H, s); 13C NMR (CDCl3)
d 164.1, 151.5,
142.0, 135.4, 134.4, 130.0, 129.9, 128.4, 121.2, 115.2, 111.3, 51.4, 42.9,
34.2, 31.7, 20.3; FAB-MS m/z 298 (MþþH, 100); FAB-HRMS calcd
for C18H19NOS 297.1187, found 297.1183.
(film) 3077, 2221, 1642, 1594, 1447, 1251 cmꢀ1 1H NMR (CDCl3)
;
d
7.51e7.39 (5H, m), 5.75e5.68 (1H, m), 5.34 (1H, d, J¼2.2 Hz),
5.17e5.15 (1H, m), 5.11 (1H, s), 4.71 (1H, dq, J¼17.4, 2.4 Hz),
3.86e3.74 (2H, m), 2.81 (1H, ddd, J¼2.2, 6.3, 16.8 Hz), 2.44e2.34
4.1.11. 2-(Phenylthio)-8-vinyl-1,6,9,9a-tetrahydroquinolizin-4-one
(6b). Using a similar condition as for compound 6a, product 6b
(28 mg, 66%) was obtained as a yellow oil: IR (film) 3093, 1652,
(3H, m), 1.81 (3H, t, J¼2.4 Hz); 13C NMR (CDCl3)
d 162.5, 151.5, 135.4,
133.9, 130.0, 129.8, 128.5, 118.9, 114.9, 79.8, 74.3, 54.0, 35.7, 34.2,
32.0, 3.6; FAB-MS m/z 298 (MþþH, 96); FAB-HRMS calcd for
C18H20NSO 298.1266, found 298.1259.
1375, 1240, 1047 cmꢀ1 1H NMR (CDCl3)
; d 7.50e7.38 (5H, m), 6.35
(1H, dd, J¼17.7, 10.8 Hz), 5.73 (1H, br s), 5.34 (1H, t, J¼0.9 Hz),
5.14e5.00 (2H, m), 4.67 (1H, br d, J¼19.8 Hz), 3.82e3.73 (1H, m),
3.67 (1H, dd, J¼19.8, 2.4 Hz), 2.84 (1H, ddd, J¼17.1, 6.6, 0.9 Hz), 2.46
(1H, ddd, J¼17.1, 6.6, 0.9 Hz), 2.35e2.27 (2H, m); 13C NMR (CDCl3)
4.1.16. 2-(Phenylthio)-7-vinyl-1,6,9,9a-tetrahydroquinolizin-4-one
(10a). Using a similar condition as for compound 6a, product 10a
(46 mg, 62% yield) was obtained as a light yellow liquid: IR (film)
d
163.9, 151.3, 137.7, 135.2, 133.5, 129.9, 129.7, 128.2, 125.2, 115.0,
111.7, 51.0, 42.6, 33.9, 29.9; ESI-MS m/z 283 (Mþ,100); ESI-HRMS m/z
3070, 1635, 1598, 1417, 1251 cmꢀ1; 1H NMR (CDCl3)
d 7.52e7.38 (5H,
calcd for C17H17NOS 283.1031, found 283.1038.
m), 6.27 (1H, dd, J¼11.1, 17.7 Hz), 5.77 (1H, d, J¼5.1 Hz), 5.36 (1H, s),
5.16 (1H, d, J¼17.7 Hz), 5.00 (1H, d, J¼11.1 Hz), 4.81 (1H, d,
J¼17.7 Hz), 3.77e3.65 (2H, m), 2.81 (1H, ddd, J¼0.9, 6.6, 17.1 Hz),
2.51e2.33 (2H, m), 2.14 (1H, br d, J¼17.7 Hz); 13C NMR (CDCl3)
4.1.12. 6-(But-2-ynyl)-1-(2-methylprop-1-enyl)-4-(phenylthio)-5,6-
dihydropyridin-2(1H)-one (7a). A mixture of compound 5b
(100 mg, 0.32 mmol) and G1 (28 mg, 0.03 mmol) in CH2Cl2 (4 mL)
was refluxed under nitrogen for 18 h. The solvent was then evap-
orated under vacuum, and the residue was purified by flash chro-
matography using ethyl acetate/hexanes (1:5) as eluent to give
compound 7a (21 mg, 21%) as a yellow oil: IR (film) 3058, 1645,
d
164.0, 151.1, 136.4, 135.3, 134.2, 130.0, 129.9, 128.3, 125.1, 115.3,
112.1, 51.3, 41.9, 33.7, 31.4; FAB-MS m/z 284 (MþþH, 62); FAB-HRMS
calcd for C17H18NSO 284.1109 (MþþH), found 284.1107.
4.1.17. 7-Isopropenyl-2-(phenylthio)-1,6,9,9a-tetrahydroquinolizin-
4-one (10b). Using a similar condition as for compound 6a, product
10b (112 mg, 82%) was obtained as a light yellow liquid: IR (film)
1420, 1243 cmꢀ1 1H NMR (CDCl3)
; d 7.54e7.40 (5H, m), 5.95e5.94
(1H, m), 5.40 (1H, d, J¼2.1 Hz), 3.68e3.60 (1H, m), 2.91 (1H, ddd,
J¼17.1, 6.3, 2.1 Hz), 2.72 (1H, dd, J¼17.1, 2.1 Hz), 2.47e2.40 (2H, m),
1.78 (3H, t, J¼2.4 Hz), 1.76 (3H, d, J¼1.2 Hz), 1.64 (3H, d, J¼1.2 Hz);
3092,1642, 1598, 1417,1255 cmꢀ1; 1H NMR (CDCl3)
d
7.52e7.27 (5H,
m), 5.87 (1H, t, J¼2.4 Hz), 5.36 (1H, s), 5.0 (1H, s), 4.91 (1H, s), 4.88

S.-S.P. Chou et al. / Tetrahedron 67 (2011) 4505e4513
4511
(1H, d, J¼19.2 Hz), 3.77e3.67 (2H, m), 2.84 (1H, ddd, J¼1.2, 6.6,
17.1 Hz), 2.49e2.43 (1H, m), 2.37 (1H, dd, J¼5.7,17.1 Hz), 2.16 (1H, br
EI-MS m/z 439 (Mþ, 6); EI-HRMS calcd for C24H25NO5S 439.1453,
found 439.1447.
d, J¼17.1 Hz), 1.88 (3H, s); 13C NMR (CDCl3)
d 163.8, 150.8, 135.3,
135.2, 129.95, 129.85, 128.4, 121.2, 115.4, 111.3, 51.3, 42.9, 33.6, 31.3,
20.5; FAB-MS m/z 298 (MþþH, 100); FAB-HRMS calcd for
C18H20NSO 298.1266, found 298.1270.
4.1.20. Dimethyl 10-methyl-4-oxo-2-(phenylthio)-4,6,11,11a-tetrahy-
dro-1H-pyrido[1,2-b]isoquinoline-7,8-dicarboxylate (13). A mixture
of compound 12b (15 mg, 0.03 mmol) and DDQ (7 mg, 0.03 mmol)
in degassed toluene (1 mL) was heated under nitrogen at 80 ꢁC for
12 h. The solvent was removed under vacuum, and the crude
product was purified by flash chromatography using ethyl acetate/
hexanes (1:1) as eluent to give compound 13 (12 mg, 80%) as
4.1.18. trans-10-Methyl-4-oxo-2-(phenylthio)-6,6a-dihydro-1H-pyr-
ido[1,2-b]isoquinoline-7,7,8,8(4H,9H,11H,11aH)-tetracarbonitrile
(11a) and cis-10-methyl-4-oxo-2-(phenylthio)-6,6a-dihydro-1H-pyr-
ido[1,2-b]isoquinoline-7,7,8,8(4H,9H,11H,11aH)-tetracarbonitrile
(11b). A mixture or compound 6a (110 mg, 0.37 mmol) and TCNE
(142 mg, 1.11 mmol) in degassed toluene (3 mL) in a sealed tube
was heated at 160 ꢁC for 23 h. The solvent was removed under
vacuum, and the crude product was purified by flash chromatog-
raphy using ethyl acetate/hexanes (1:1) as eluent to give compound
11a (42 mg, 27%) as a white solid and compound 11b (57 mg, 36%)
as a yellow oil. Compound 11a: mp 193e195 ꢁC (recryst from
a yellow oil: IR (film) 3053, 1733, 1647, 1239, 1046 cmꢀ1
;
1H NMR
(CDCl3) 7.67 (1H, s), 7.53e7.40 (5H, m), 5.35 (1H, s), 5.13 (1H, d,
d
J¼17.4 Hz), 4.36 (1H, d, J¼17.4 Hz), 3.94 (3H, s), 3.85 (3H, s),
2.97e2.85 (2H, m), 2.76 (1H, dd, J¼16.5, 4.2 Hz), 2.50 (1H, dd, J¼17.1,
6.0 Hz), 2.30 (3H, s); 13C NMR (CDCl3)
d 168.8, 166.3, 163.0, 151.3,
138.0, 137.7, 135.4, 131.7, 131.3, 130.1, 129.9, 129.4, 128.2, 126.2, 115.1,
52.9, 52.5, 51.3, 42.3, 33.7, 32.1, 19.4; EI-MS m/z 437 (Mþ, 10); EI-
HRMS calcd for C24H23NO5S 437.1297, found 437.1300.
CH2Cl2/hexanes); IR (film) 3055, 2306, 1648, 1422, 1266 cmꢀ1
;
1H
NMR (600 MHz, CDCl3) 7.51e7.44 (5H, m), 5.34 (1H, s), 5.03
d
d
d
4.1.21. endo-trans-5-Methyl-2-phenyl-8-(phenylthio)-3a,4,6a,7,12,
12a-hexahydropyrido[1,2-b]pyrrolo[3,4-h]isoquinoline-
1,3,10(2H,6H,12bH)-trione (14a) and endo-cis-5-methyl-2-phenyl-
8-(phenylthio)-3a,4,6a,7,12,12a-hexahydropyrido[1,2-b]pyrrolo
[3,4-h]isoquinoline-1,3,10(2H,6H,12bH)-trione (14b). A mixture of
compound 6a (100 mg, 0.34 mmol) and N-phenylmaleimide
(175 mg, 1.02 mmol) in degassed toluene (3 mL) was heated at
160 ꢁC for 4 h. The solvent was removed under vacuum, and the
crude product was purified by flash chromatography using ethyl
acetate/hexanes (1:1) as eluent to give a mixture of compounds
14a and 14b (143 mg, 90%; 62:38 by 1H NMR). With repeated
separation by flash chromatography, pure samples of 14a and
14b were obtained. Compound 14a: a yellow oil; IR (film) 3057,
(1H, dd, J¼12.6, 4.8 Hz), 3.59e3.54 (1H, m), 3.18 (1H, d, J¼18.6 Hz),
3.09e3.07 (1H, m), 2.96e2.91 (2H, m), 2.79e2.72 (2H, m), 2.42 (1H,
dd, J¼17.4, 6.0 Hz), 2.20 (1H, dd, J¼13.8 Hz), 1.88 (3H, s); 13C NMR
(150 MHz, CDCl3)
d 163.8, 153.5, 135.4, 130.3, 130.0, 127.5, 124.9,
122.9,113.8,110.8,110.3,110.1,108.8, 54.0, 44.9, 41.9, 40.3, 38.0, 37.3,
33.8, 33.5, 18.8; EI-MS m/z 425 (Mþ, 53); EI-HRMS calcd for
C24H19N5OS 425.1310, found 425.1305. Compound 11b: IR (film)
3055, 2306, 1647, 1423, 1266 cmꢀ1 1H NMR (600 MHz, CDCl3)
;
d
7.49e7.43 (5H, m), 5.39 (1H, d, J¼1.8 Hz), 4.42 (1H, dd, J¼13.2,
4.8 Hz), 4.04e3.99 (1H, m), 3.75 (1H, dd, J¼13.2, 8.4 Hz), 3.39 (1H,
br s), 3.16 (1H, d, J¼18.6 Hz), 3.05 (1H, d, J¼18.6 Hz), 2.69 (1H, br d,
J¼16.2 Hz), 2.57e2.51 (2H, m), 2.35 (1H, dd, J¼16.2, 4.2 Hz), 1.82
(3H, s); 13C NMR (150 MHz, CDCl3)
d
163.3, 153.1, 135.2, 130.2, 129.9,
1703, 1630, 1381, 1187 cmꢀ1 1H NMR (600 MHz, CDCl3)
;
127.8, 124.1, 123.1, 114.8, 110.7, 110.5, 110.3, 108.1, 50.8, 41.5, 40.8,
39.2, 38.7, 37.6, 35.2, 32.0, 18.1; EI-MS m/z 425 (Mþ, 50); EI-HRMS
calcd for C24H19N5OS 425.1310, found 425.1306.
d
7.48e7.36 (8H, m), 7.14e7.12 (2H, m), 5.34 (1H, d, J¼1.8 Hz), 4.63
(1H, dd, J¼13.8, 6.0 Hz), 4.03e4.01 (1H, m), 3.73 (1H, dd, J¼13.8,
12.0 Hz), 3.30e3.24 (2H, m), 2.69 (1H, dd, J¼15.0, 1.2 Hz), 2.56
(2H, br s), 2.49e2.40 (2H, m), 2.33 (1H, br d), 2.23 (1H, dd, J¼16.8,
4.1.19. trans-Dimethyl 10-methyl-4-oxo-2-(phenylthio)-4,6,6a,9,11,11a-
hexahydro-1H-pyrido[1,2-b]isoquinoline-7,8-dicarboxylate (12a) and
cis-dimethyl10-methyl-4-oxo-2-(phenylthio)-4,6,6a,9,11,11a-hexahydro-
1H-pyrido[1,2-b]isoquinoline-7,8-dicarboxylate (12b). A mixture of
compound 6a (50 mg, 0.17 mmol) and DMAD (0.13 mL, 1.02 mmol)
in degassed toluene (2 mL) was heated under nitrogen at 80 ꢁC for
48 h. The solvent was removed under vacuum, and the crude
product was purified by flash chromatography using ethyl acetate/
hexanes (1:1) as eluent to give compound 12a (25 mg, 34%) as
a white solid and compound 12b (24 mg, 32%) as a yellow oil.
Compound 12a: mp 169e171 ꢁC (recryst from CH2Cl2/hexanes); IR
4.8 Hz), 1.78 (3H, s); 13C NMR (150 MHz, CDCl3)
d 178.5, 176.8,
163.0, 152.3, 135.2, 131.8, 130.6, 129.9, 129.8, 129.2, 128.7, 128.3,
127.7, 126.4, 115.2, 51.9, 42.2, 40.8, 38.2, 38.0, 35.5, 31.4, 29.1, 18.9;
EI-MS m/z 470 (Mþ, 4); EI-HRMS calcd for C28H26N2O3S 470.1664,
found 470.1664. Compound 14b: a yellow oil; IR (film) 3058, 1737,
1709, 1639, 1374, 1239, 1046 cmꢀ1 1H NMR (600 MHz, CDCl3)
;
d
7.49e7.36 (8H, m), 7.16e7.15 (2H, m), 5.40 (1H, d, J¼2.4 Hz),
4.64 (1H, dd, J¼13.8, 5.4 Hz), 3.86 (1H, dd, J¼13.8, 12.6 Hz),
3.68e3.64 (1H, m), 3.27e3.22 (2H, m), 2.70 (1H, dd, J¼14.4,
1.2 Hz), 2.64 (1H, dd, J¼14.4, 3.0 Hz), 2.63 (1H, br s), 2.51 (1H,
ddd, J¼16.2, 13.8, 2.1 Hz), 2.33e2.30 (2H, m), 2.24 (1H, dd, J¼16.8,
(film) 3058, 1721, 1639, 1434, 1264 cmꢀ1
;
1H NMR (CDCl3)
3.6 Hz), 1.78 (3H, s); 13C NMR (150 MHz, CDCl3)
d 178.5, 176.5,
d
7.51e7.40 (5H, m), 5.32 (1H, d, J¼1.2 Hz), 4.64 (1H, dd, J¼15.6,
163.4, 152.4, 135.2, 131.8, 129.9, 129.8, 129.1, 128.6, 128.54, 128.45,
128.2, 126.4, 116.0, 53.1, 42.2, 40.0, 37.6, 36.1, 35.9, 31.0, 30.4, 19.1;
EI-MS m/z 470 (Mþ, 0.1); EI-HRMS calcd for C28H26N2O3S
470.1664, found 470.1660.
3.9 Hz), 3.82 (3H, s), 3.77 (3H, s), 3.48e3.38 (1H, m), 3.17e3.13 (1H,
m), 3.06 (1H, dd, J¼23.1, 6.9 Hz), 2.87 (1H, dd, J¼22.5, 6.0 Hz), 2.76
(1H, dd, J¼13.5, 3.3 Hz), 2.65 (1H, dd, J¼17.1, 5.7 Hz), 2.48 (1H, ddd,
J¼17.1, 9.6, 1.5 Hz), 2.33 (1H, dd, J¼12.0, 11.7 Hz), 1.95 (1H, t,
J¼12.3 Hz), 1.72 (3H, s); 13C NMR (150 MHz, CDCl3)
d
167.8, 167.7,
4.1.22. endo-trans-2,5-Dimethyl-8-(phenylthio)-3a,4,6a,7,12,12a-
h e x a h y d r o p y r i d o [ 1, 2 - b ] p y r r o l o [ 3 , 4 - h ] i s o q u i n o l i n e -
1,3,10(2H,6H,12bH)-trione (15a) and endo-cis-2,5-dimethyl-8-(phe-
nylthio)-3a,4,6a,7,12,12a-hexahydropyrido[1,2-b]pyrrolo[3,4-h]iso-
quinoline-1,3,10(2H,6H,12bH)-trione (15b). A mixture of compound
6a (111 mg, 0.37 mmol) and N-methylmaleimide (123 mg,
1.11 mmol) in degassed toluene (3 mL) was heated at 160 ꢁC for 4 h.
The solvent was removed under vacuum, and the crude product
was purified by flash chromatography using ethyl acetate/hexanes
(1:1) as eluent to give a mixture of compounds 15a and 15b
(121 mg, 80%; 66:34 by 1H NMR). With repeated separation by flash
chromatography, pure samples of 15a and 15b were obtained.
164.7, 152.3, 135.3, 133.8, 132.6, 130.0, 129.8, 128.1, 125.0, 121.9,
114.9, 55.7, 52.5, 52.3, 47.9, 39.4, 35.5, 35.1, 33.7, 17.7; EI-MS m/z
439 (Mþ, 6); EI-HRMS calcd for C24H25NO5S 439.1453, found
439.1447; Compound 12b: IR (film) 3053, 1721, 1637, 1433,
1264 cmꢀ1 1H NMR (CDCl3)
; d 7.51e7.39 (5H, m), 5.36 (1H, d,
J¼1.2 Hz), 4.11 (1H, dd, J¼12.3, 4.8 Hz), 4.05e3.94 (1H, m), 3.80
(3H, s), 3.76 (3H, s), 3.59e3.51 (1H, m), 3.20 (1H, t, J¼12.3 Hz), 3.06
(1H, dd, J¼22.8, 7.5 Hz), 2.87 (1H, dd, J¼22.8, 9.0 Hz), 2.60 (1H, br
d, J¼15.0 Hz), 2.53e2.37 (3H, m), 1.67 (3H, s); 13C NMR (CDCl3)
d
167.8, 167.7, 164.7, 152.3, 135.3, 133.8, 132.6, 130.0, 129.8, 128.1,
125.0, 121.9, 114.9, 55.7, 52.5, 52.3, 47.9, 39.4, 35.5, 35.1, 33.7, 17.7;

4512
S.-S.P. Chou et al. / Tetrahedron 67 (2011) 4505e4513
Compound 15a: a yellow oil; IR (film) 3055, 1693, 1632, 1430 cmꢀ1
1H NMR (CDCl3)
(1H, dd, J¼13.5, 6.0 Hz), 4.02e3.94 (1H, m), 3.72 (1H, dd, J¼13.5,
11.4 Hz), 3.14e3.05 (2H, m), 2.90 (3H, s), 2.59 (1H, dd, J¼15.3,
1.5 Hz), 2.47e2.35 (4H, m), 2.26e2.19 (2H, m), 1.70 (3H, s); 13C NMR
;
product was purified by flash chromatography using ethyl acetate/
hexanes (1:1) as eluent to give a mixture of compounds 18a and 18b
(123 mg, 69%; 80:20 by 1H NMR) as a light yellow solid: mp
d
7.50e7.37 (5H, m), 5.33 (1H, d, J¼2.1 Hz), 4.57
137e139 ꢁC; IR (film) 3062, 1708, 1635, 1587, 1384, 1185 cmꢀ1 1H
;
NMR (CDCl3)
d 7.43e7.35 (8H, m), 7.17e7.09 (2H, m), 5.36 (1H, d,
(CDCl3)
d
179.4, 177.8, 163.0, 152.2, 135.2, 130.4, 129.9, 129.8, 128.5,
J¼2.1 Hz), 5.11 (0.2H, d, J¼15.9 Hz), 5.00 (0.8H, d, J¼15 Hz), 4.11e4.04
(1H, m), 3.42 (1H, d, J¼15 Hz), 3.32e3.19 (2H, m), 2.78e2.57 (4H, m),
2.35e2.21 (2H, m), 2.04e1.94 (1H, m), 1.81 (3H, s); FAB-MS m/z 471
(MþþH, 98); FAB-HRMS calcd for C28H27N2SO3 471.1742, found
471.1736. The mixture of 18a and 18b was recrystallized from CH2Cl2/
hexanes to give some pure compound 18a: 1H NMR (CDCl3)
127.4, 115.4, 52.0, 42.1, 40.7, 38.2, 37.9, 35.5, 30.9, 29.2, 24.9, 19.0; EI-
MS m/z 408 (Mþ, 100); EI-HRMS calcd for C23H24N2O3S 408.1508,
found 408.1504. Compound 15b: a yellow oil; IR (film) 3055, 1693,
1632, 1431 cmꢀ1; 1H NMR (CDCl3)
d 7.50e7.39 (5H, m), 5.39 (1H, d,
J¼2.4 Hz), 4.62 (1H, dd, J¼13.8, 5.4 Hz), 3.81 (1H, dd, J¼13.8,
12.6 Hz), 3.68e3.60 (1H, m), 3.15e3.05 (2H, m), 2.91 (3H, s),
2.63e2.45 (4H, m), 2.31e2.19 (3H, m), 1.71 (3H, s); 13C NMR (CDCl3)
d
7.50e7.36 (8H, m), 7.17e7.14 (2H, m), 5.36 (1H, d, J¼2.1 Hz), 5.00
(1H, d, J¼15.3 Hz), 4.10e4.06 (1H, m), 3.42 (1H, d, J¼15.3 Hz),
3.32e3.20 (2H, m), 2.79e2.58 (4H, m), 2.34e2.21 (2H, m), 2.03e1.96
d
179.5, 177.5, 163.5, 152.2, 135.3, 129.9 (ꢂ2), 128.6, 128.3, 128.1,
116.3, 53.2, 42.0, 39.9, 37.7, 36.0, 35.9, 30.7, 30.6, 25.0, 19.2; EI-MS
m/z 408 (Mþ, 43); EI-HRMS calcd for C23H24N2O3S 408.1508,
found 408.1506.
(1H, m), 1.80 (3H, s); 13C NMR (CDCl3)
d 178.4, 177.1, 163.0, 152.5,
135.3, 131.9, 130.0, 129.9, 129.4, 129.3, 128.8, 128.6, 128.0, 126.5, 115.8,
50.8, 43.7, 40.1, 37.6, 34.3, 31.6, 30.8, 28.8, 19.3.
4.1.23. 2-Phenyl-9-(phenylthio)-3a,4,6,10,10a,11,11a,11b-octahydro-
2,6a-diaza-cyclopenta[a]anthracene-1,3,7-trione (16). A mixture of
compound 10a (58 mg, 0.20 mmol) and N-phenylmaleimide
(106 mg, 0.60 mmol) in degassed toluene (3 mL) was heated at
80 ꢁC for 13 h. The solvent was removed under vacuum, and the
crude product was purified by flash chromatography using ethyl
acetate/hexanes (1:1) as eluent to give a mixture of compounds 16a
and 16b (61 mg, 65%; 78:22 by 1H NMR) as a light yellow solid: mp
4.1.26. 2,5-Dimethyl-9-(phenylthio)-3a,4,6,10,10a,11,11a,11b-octahy-
dro-2,6a-diaza-cyclopenta[a]anthracene-1,3,7-trione (19). A mix-
ture of compound 10b (60 mg, 0.20 mmol) and N-methylmaleimide
(67 mg, 0.60 mmol) in degassed toluene (3 mL) was heated at 80 ꢁC
for 13 h. The solvent was removed under vacuum, and the crude
product was purified by flash chromatography using ethyl acetate/
hexanes (1:1) as eluent to give a mixture of compounds 19a and
19b (56 mg, 68%; 75:25 by 1H NMR) as a light yellow solid: mp
97e99 ꢁC; IR (film) 3062, 1705, 1631, 1583, 1380, 1185 cmꢀ1
;
1H
157e159 ꢁC; IR (film) 3055, 1697, 1635, 1587, 1432 cmꢀ1
(CDCl3)
;
1H NMR
NMR (CDCl3) 7.40e7.35 (8H, m), 7.20e7.14 (2H, m), 5.84 (1H, d,
d
d
7.50e7.38 (5H, m), 5.34 (1H, d, J¼1.2 Hz), 5.03 (0.25H, d,
J¼6.9 Hz), 5.35 (1H, d, J¼1.4 Hz), 4.74 (0.22H, d, J¼15.9 Hz), 4.60
(0.78H, d, J¼15.0 Hz), 4.08e3.98 (1H, m), 3.67 (1H, d, J¼15.6 Hz),
3.33e3.25 (2H, m), 2.85 (1H, dd, J¼7.5, 15.6 Hz), 2.79e2.58 (3H, m),
2.28e2.21 (2H, m), 2.09e1.91 (1H, m); FAB-MS m/z 457 (MþþH,
53); FAB-HRMS calcd for C27H25N2SO3 457.1586, found 457.1590.
J¼15.9 Hz), 4.88 (0.75H, d, J¼15.3 Hz), 4.10e4.02 (1H, m), 3.41 (1H,
d, J¼15.3 Hz), 3.11e3.02 (2H, m), 2.93 (2.3H, s), 2.91 (0.8H, s),
2.74e2.54 (4H, m), 2.26e2.18 (2H, m), 1.97e1.89 (1H, m), 1.80e1.73
(4H, m); FAB-MS m/z 409 (MþþH, 100); FAB-HRMS calcd for
C23H25N2SO3 409.1586, found 409.1579. Compound 19a: 13C NMR
Compound 16a: 13C NMR (CDCl3)
d
178.4, 176.9, 163.0, 152.6, 136.7,
(CDCl3) d 179.3, 178.0, 163.0, 152.4, 135.3, 129.9, 129.8, 129.1, 128.6,
135.3, 131.8, 130.0, 129.9, 129.3, 128.8, 128.5, 126.5, 121.6, 115.7, 51.0,
43.1, 41.7, 40.0, 34.5, 30.7, 28.6, 24.1.
127.7, 115.8, 50.7, 43.3, 39.9, 37.4, 34.4, 31.2, 30.3, 28.8, 25.1, 19.3.
4.1.27. exo-trans-6-Methyl-4a-(phenylsulfonyl)-10-(phenylthio)-2-
tosyl-3,4,4a,5,7,11,11a,12,12a,12b-decahydro-2,7a-diaza-cyclohexa[a]
anthracene-1,8-dione (21). A mixture of compound 10b (40 mg,
0.13 mmol) and compound 20 (158 mg, 0.40 mmol) in degassed
toluene (2 mL) was heated at 160 ꢁC for 48 h. The solvent was re-
moved under vacuum, and the crude product was purified by flash
chromatography using ethyl acetate/hexanes (1:1) as eluent to give
compound 21 (43 mg, 47% yield) as a white solid: mp 242e244 ꢁC
(recryst from CH2Cl2/hexanes); IR (film) 3062, 1697, 1642, 1590,
4.1.24. 2-Methyl-9-(phenylthio)-3a,4,6,10,10a,11,11a,11b-octahydro-
2,6a-diaza-cyclopenta[a]anthracene-1,3,7-trione (17). A mixture of
compound 10a (62 mg, 0.22 mmol) and N-methylmaleimide
(73 mg, 0.66 mmol) in degassed toluene (2 mL) was heated at 80 ꢁC
for 13 h. The solvent was removed under vacuum, and the crude
product was purified by flash chromatography using ethyl acetate/
hexanes (1:1) as eluent to give a mixture of compounds 17a and 17b
(55 mg, 64%; 71:29 by 1H NMR) as a light yellow solid: mp
95e96 ꢁC; IR (film) 3062, 1694, 1635, 1587, 1432 cmꢀ1
;
1H NMR
7.49e7.38 (5H, m), 5.76 (1H, br), 5.34 (1H, d, J¼2.1 Hz),
1358, 1144 cmꢀ1
;
1H NMR (CDCl3)
d
8.00 (2H, d, J¼8.2 Hz),
(CDCl3)
d
7.79e7.55 (5H, m), 7.52e7.40 (5H, m), 7.36 (2H, d, J¼8.2 Hz), 5.29
(1H, d, J¼2.4 Hz), 4.89 (1H, d, J¼17.1 Hz), 4.36e4.31 (1H, m),
4.20e4.10 (1H, m), 3.84e3.78 (1H, m), 3.41 (1H, d, J¼17.1 Hz),
2.66e2.54 (2H, m), 2.45 (3H, s), 2.41e2.26 (4H, m), 2.17 (1H, dd,
J¼4.5, 17.1 Hz), 2.00e1.94 (2H, m), 1.71e1.64 (1H, m), 1.55 (3H, s);
4.69 (0.29H, d, J¼15.9 Hz), 4.53 (0.71H, d, J¼15.0 Hz), 4.04e3.97
(1H, m), 3.63 (1H, d, J¼13.5 Hz), 3.15e3.12 (2H, m), 2.94 (2H, s), 2.92
(1H, s), 2.81e2.67 (2H, m), 2.63e2.55 (2H, m), 2.35e2.12 (2H, m),
2.05e1.92 (1H, m); FAB-MS m/z 395 (MþþH, 76); FAB-HRMS calcd
for C22H23N2SO3 395.1429, found 395.1433. The mixture of 17a and
17b was recrystallized from CH2Cl2/hexanes to give some pure
13C NMR (CDCl3)
d 170.5, 164.3, 153.7, 144.8, 135.6, 135.5, 134.7,
134.2, 130.7, 130.1, 130.0 (x2), 129.4, 128.9, 128.4, 124.0, 121.6, 114.8,
64.2, 50.8, 47.0, 44.4, 39.8, 36.5, 34.9, 34.4, 31.8, 23.7, 21.9, 18.2; FAB-
MS m/z 689 (MþþH, 100); FAB-HRMS calcd for C36H37N2S3O6
689.1814, found 689.1819.
compound 17a: 1H NMR (CDCl3)
d 7.50e7.40 (5H, m), 5.75 (1H, br),
5.33 (1H, d, J¼2.1 Hz), 4.53 (1H, d, J¼15.0 Hz), 4.05e3.98 (1H, m),
3.63 (1H, d, J¼15 Hz), 3.15e3.13 (2H, m), 2.95 (3H, s), 2.81e2.71 (2H,
m), 2.68e2.58 (2H, m), 2.23 (1H, dd, J¼4.5, 16.5 Hz), 2.17e2.12 (1H,
m), 1.76 (1H, dt, J¼4.5, 14.4 Hz); 13C NMR (CDCl3)
d
179.4, 177.9,
4.1.28. 2-(Phenylthio)-7-vinyl-1,6,9,9a-tetrahydroquinolizin-4-N-to-
syl-imine (22a). A mixture of compound 9a (84 mg, 0.31 mmol)
and PTSI (0.18 mL, 1.24 mmol) in toluene (1.5 mL) was heated in
a sealed tube at 120 ꢁC for 6 h. After cooling in an ice bath, 5% aq
NaOH was slowly added to decompose the excess PTSI. The reaction
mixture was extracted with ethyl acetate (50 mLꢂ3), and the or-
ganic solution was washed with 5% aq NaOH (30 mLꢂ3). The sol-
vent was removed under vacuum, and the residue was purified by
flash chromatography using ethyl acetate/hexanes (1:3) as eluent
163.0, 152.4, 136.6, 135.3, 130.0, 129.9, 128.7, 121.5, 115.8, 51.0, 43.0,
41.7, 39.9, 34.6, 30.6, 28.7, 25.1, 23.8.
4.1.25. 5-Ethyl-2-phenyl-9-(phenylthio)-3a,4,6,10,10a,11,11a,11b-octa-
hydro-2,6a-diaza-cyclopenta[a]anthracene-1,3,7-trione (18). A mix-
ture of compound 10b (112 mg, 0.37 mmol) and N-phenylmaleimide
(196 mg, 1.11 mmol) in degassed toluene (5 mL) was heated at 80 ꢁC
for 13 h. The solvent was removed under vacuum, and the crude

S.-S.P. Chou et al. / Tetrahedron 67 (2011) 4505e4513
4513
to give compound 22a (54 mg, 40%) as a light yellow solid: mp
144e146 ꢁC (recryst from CH2Cl2/hexanes); IR (film) 3062, 1734,
157.2, 154.8, 141.6, 141.1, 135.4, 131.8, 131.4, 130.5, 130.1, 129.3,
129.1, 128.8, 127.6, 126.8, 126.5, 126.4, 110.1, 52.3, 42.1, 40.9 (ꢂ2),
37.8, 34.8, 31.6, 29.0, 21.5, 19.0; FAB-MS m/z 624 (MþþH, 33); FAB-
HRMS calcd for C35H33N3O4S2 623.1912, found 623.1907. Com-
pound 24b: a yellow oil; IR (film) 3063, 1707, 1599, 1499 cmꢀ1; 1H
1601, 1502, 1461, 1439 cmꢀ1 1H NMR (CDCl3)
; d 7.55e7.51 (5H, m),
7.48 (2H, d, J¼8.1 Hz), 7.11 (2H, d, J¼8.1 Hz), 6.44 (1H, s), 6.25 (1H,
dd, J¼11.1, 17.8 Hz), 5.77 (1H, d, J¼5.1 Hz), 5.13 (1H, d, J¼17.8 Hz),
5.02 (1H, d, J¼11.1 Hz), 4.88 (1H, d, J¼17.9 Hz), 3.83 (1H, d,
J¼17.9 Hz), 3.75e3.68 (1H, m), 2.76 (1H, dd, J¼6.6, 17.1 Hz),
2.49e2.34 (2H, m), 2.36 (3H, s), 2.18 (1H, dt, J¼17.7, 4.8 Hz); 13C
NMR (CDCl3)
d 7.48e7.35 (10H, m), 7.15e7.09 (4H, m), 6.46 (1H, d,
J¼2.4 Hz), 4.98 (1H, dd, J¼14.4, 5.4 Hz), 3.95 (1H, t, J¼13.2 Hz),
3.62e3.53 (1H, m), 3.32e3.25 (2H, m), 2.73e2.68 (1H, m),
2.64e2.55 (2H, m), 2.51e2.45 (1H, m), 2.37e2.33 (4H, m), 2.31
(1H, s), 2.23 (1H, dd, J¼16.5, 3.9 Hz), 1.77 (3H, s); 13C NMR (CDCl3)
NMR (CDCl3)
d 157.4, 152.9, 141.6, 141.1, 135.9, 135.3, 133.8, 130.4,
130.1, 129.0, 127.5, 126.3, 124.6, 112.7, 109.9, 51.5, 44.5, 33.2, 31.1,
21.5; FAB-MS m/z 437 (MþþH, 67); FAB-HRMS calcd for
C24H25N2S2O2 437.1357, found 437.1367.
d
178.4, 176.5, 157.7, 154.6, 141.6, 141.1, 135.3, 131.8, 130.5, 130.1,
129.2, 129.0, 128.8, 128.6, 127.8, 127.6, 126.5, 126.4, 110.7, 53.5,
42.0, 40.2, 39.9, 35.8, 35.2, 31.3, 30.2, 21.5, 19.1; FAB-MS m/z 624
(MþþH, 20); FAB-HRMS calcd for C35H33N3O4S2 623.1912, found
623.1914.
4.1.29. 7-Isopropenyl-2-(phenylthio)-1,6,9,9a-tetrahydroquinolizin-
4-N-tosyl-imine (22b). Using a similar condition as for compound
22a, product 22b (79 mg, 48% yield) was obtained as a yellow solid:
mp 143e145 ꢁC (recryst from CH2Cl2/hexanes); IR (film) 3062, 1730,
Acknowledgements
1601, 1505, 1461, 1439 cmꢀ1 1H NMR (CDCl3)
; d 7.55e7.52 (5H, m),
7.48 (2H, d, J¼8.1 Hz), 7.11 (2H, d, J¼8.1 Hz), 6.45 (1H, s), 5.86 (1H, d,
J¼4.8 Hz), 4.98e4.92 (3H, m), 3.87 (1H, d, J¼17.7 Hz), 3.74e3.67
(1H, m), 2.77 (1H, dd, J¼6.9, 17.4 Hz), 2.51e2.33 (2H, m), 2.36 (3H,
Financial support of this work by the National Science Council of
the Republic of China (NSC 97-2113-M-030-001-MY3) and Fu Jen
Catholic University (9991A15/10973104995-4) is gratefully
acknowledged.
s), 2.19 (1H, dt, J¼17.1, 4.5 Hz), 1.87 (3H, s); 13C NMR (CDCl3)
d 157.3,
152.7, 141.5, 141.2, 140.1, 135.3, 135.0, 130.4, 130.1, 129.0, 127.6, 126.3,
120.8, 111.8, 110.0, 51.3, 45.5, 33.1, 31.1, 21.5, 20.6; FAB-MS m/z 451
(MþþH, 83); FAB-HRMS calcd for C25H27N2S2O2 451.1514, found
451.1522. Anal. Calcd for C25H26N2S2O2: C, 66.63; H, 5.82; N, 6.22.
Found: C, 66.39; H, 5.51; N, 6.24.
Supplementary data
1H and 13C NMR spectra for all compounds reported in this
article. Supplementary data associated with this article can be
found in online version at doi:10.1016/j.tet.2011.04.106.
4.1.30. (E)-4-Methyl-N-(2-(phenylthio)-8-(prop-1-en-2-yl)-1H-qui-
nolizin-4(6H,9H,9aH)-ylidene)benzenesulfonamide (23). A mixture
of compound 6a (100 mg, 0.34 mmol) and PTSI (0.21 mL,
1.36 mmol) in degassed toluene (3 mL) was heated in a sealed tube
at 160 ꢁC for 3 h. The solvent was removed under vacuum, and the
residue was purified by flash chromatography using ethyl acetate/
hexanes (1:3) as eluent to give compound 23 (81 mg, 53%) as
References and notes
1. For reviews, see: (a) Diver, S. T.; Giessert, A. J. Chem. Rev. 2004, 104, 1317e1382;
(b) Maifeld, S. V.; Lee, D. Chem.dEur. J. 2005, 11, 6118e6126; (c) Schmidt, C.;
Hermanns, J. Curr. Org. Chem. 2006, 10, 1363e1396; (d) Villar, H.; Fringsa, M.;
Bolm, C. Chem. Soc. Rev. 2007, 36, 55e66; (e) Majumdar, K. C.; Muhuri, S.; Islam,
R. U.; Chattopadhyay, B. Heterocycles 2009, 78, 1109e1169.
2. For some selected syntheses, see: (a) Kim, S.-H.; Bowden, N.; Grubbs, R. H. J. Am.
Chem. Soc. 1994, 116, 10801e10802; (b) Renaud, J.; Graf, C. D.; Oberer, L. Angew.
Chem., Int. Ed. 2000, 39, 3101e3104; (c) Moreno-Manas, M.; Pleixats, R.; San-
tamaria, A. Synlett 2001, 1784e1786.
3. For some selected syntheses, see: (a) Rosillo, M.; Casarrubios, L. ,; Dominguez,
G.; Perez-Castells, J. Tetrahedron Lett. 2001, 42, 7029e7031; (b) Saito, N.; Sato,
Y.; Mori, M. Org. Lett. 2002, 4, 803e805; (c) Katritzky, A. R.; Nair, S. K.;
Khokhlova, T.; Akhmedov, N. G. J. Org. Chem. 2003, 68, 5724e5727; (d) Ma, S.;
Ni, b.; Liang, Z. J. Org. Chem. 2004, 69, 6305e6309; (e) Ben-Othman, R.; Othman,
M.; Coste, S.; Decroix, B. Tetrahedron 2008, 64, 559e567; (f) Kobayashi, S.;
Furuya, T.; Otani, T.; Saito, T. Tetrahedron Lett. 2008, 49, 4513e4515; (g) Yang, Q.;
Lai, Y.-Y.; Xiao, W.-J.; Alper, H. Tetrahedron Lett. 2008, 49, 7334e7336; (h)
Sridharan, V.; Maiti, S.; Menendez, J. C. J. Org. Chem. 2009, 74, 9365e9371.
4. (a) Chou, S. S. P.; Hung, C. C. Tetrahedron Lett. 2000, 41, 8323e8326; (b) Chou, S.
S. P.; Hung, C. C. Synthesis 2001, 2450e2462.
5. (a) Chou, S. S. P.; Chiu, H. C.; Hung, C. C. Tetrahedron Lett. 2003, 44, 4653e4655;
(b) Chou, S. S. P.; Ho, C. W. Tetrahedron Lett. 2005, 46, 8551e8554; (c) Chou, S. S.
P.; Liang, C. F.; Lee, T. M.; Liu, C. F. Tetrahedron 2007, 63, 8267e8273; (d) Chou,
S. S. P.; Liu, C. F. J. Chin. Chem. Soc. 2010, 57, 811e819; (e) Chou, S. S. P.; Cai, Y. L.
Tetrahedron 2011, 67, 1183e1186; (f) Chou, S. S. P.; Chung, Y. C.; Chen, P. A.;
Chiang, S. L.; Wu, C. J. J. Org. Chem. 2011, 76, 692e695; (g) Chou, S. S. P.; Yang, T.
H.; Wu, W. S.; Chiu, T. H. Synthesis 2011, 759e763.
6. (a) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, NY, 1986; Vol. 3; Chapter 1, pp 1e274; (b)
Daly, J. W.; Garraffo, H. M.; Spande, T. F. In Alkaloids: Chemical and Biological
Perspectives; Pelletier, S. W., Ed.; Pergamon: New York, NY,1999; Vol.13, pp 1e161.
7. (a) Gundermann, K. D.; Holtman, P. Angew. Chem., Int. Ed. Engl. 1966, 5, 668; (b)
Hopkins, P. B.; Fuchs, P. L. J. Org. Chem. 1978, 43, 1208e1217.
8. Parsons, A. F.; Pettifer, R. M. Tetrahedron Lett. 1996, 37, 1667e1670.Crystallo-
graphic data (excluding structure factors) for compounds, Crystallographic data
(excluding structure factors) for compounds 11a, 12a, 21, and 22bin this paper
have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC 813314 (compound 11a), 813315 (compound
12a), 813313 (compound 21), 813312 (compound 22b). Copies of the data can
be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: þ44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
9. Chou, S. S. P.; Chen, P. W. Tetrahedron 2008, 64, 1879e1887.
a yellow liquid: IR (film) 3048, 1604, 1507, 1462, 1435 cmꢀ1
NMR (CDCl3)
;
1H
d
7.57e7.50 (5H, m), 7.46 (2H, d, J¼8.1 Hz), 7.12 (2H, d,
J¼8.1 Hz), 6.42 (1H, s), 5.76 (1H, d, J¼1.2 Hz), 4.95 (2H, s), 4.71 (1H,
br d, J¼20.1 Hz), 3.88 (1H, br d, J¼20.1 Hz), 3.77e3.72 (1H, m), 2.74
(1H, dd, J¼17.1, 6.3 Hz), 2.52e2.46 (1H, m), 2.42e2.39 (2H, m), 2.37
(3H, s), 1.89 (3H, s); 13C NMR (CDCl3)
d 157.4, 153.4, 141.6, 141.5,
141.1, 135.4, 134.3, 130.5, 130.1, 129.0, 127.5, 126.4, 120.3, 111.8, 109.8,
51.4, 45.3, 33.8, 31.6, 21.5, 20.2; FAB-MS m/z 451 (MþþH, 100); FAB-
HRMS calcd for C25H26N2O2S2 450.1436, found 450.1428.
4.1.31. endo-trans-(E)-4-Methyl-N-(5-methyl-1,3-dioxo-2-phenyl-8-
(phenylthio)-1,2,3,3a,4,6a,7,12,12a,12b-decahydropyrido[1,2-b]pyrrolo
[3,4-h]isoquinolin-10(6H)-ylidene)benzenesulfonamide (24a) and
endo-cis-(E)-4-methyl-N-(5-methyl-1,3-dioxo-2-phenyl-8-(phenyl-
thio)-1,2,3,3a,4,6a,7,12,12a,12b-decahydropyrido[1,2-b]pyrrolo[3,4-
h]isoquinolin-10(6H)-ylidene)benzenesulfonamide (24b). A mix-
ture of compound 23 (30 mg, 0.07 mmol) and N-phenylmaleimide
(35 mg, 0.21 mmol) in degassed toluene (2.5 mL) was heated in
a sealed tube at 160 ꢁC for 4 h. The solvent was removed under
vacuum, and the crude product was purified by flash chroma-
tography using ethyl acetate/hexanes (1:1) as eluent to give
a mixture of compounds 24a and 24b (34 mg, 82%; 59:41 by 1H
NMR) as a yellow oil. With repeated separation by flash chroma-
tography, pure samples of 24a and 24b were obtained. Compound
24a: a yellow oil; IR (film) 3057, 1707, 1599, 1500 cmꢀ1
;
1H NMR
(CDCl3) 7.51e7.35 (10H, m), 7.13e7.09 (4H, m), 6.24 (1H, d,
d
J¼1.8 Hz), 4.95 (1H, dd, J¼13.8, 6.0 Hz), 3.97e3.91 (1H, m), 3.81
(1H, t, J¼12.0 Hz), 3.34e3.25 (2H, m), 2.70 (1H, dd, J¼15.6, 1.2 Hz),
2.64e2.43 (4H, dd, J¼13.8, 6.0 Hz), 2.39e2.32 (4H, m), 2.23 (1H,
10. Hamley, P.; Holmes, A. B.; Kee, A.; Ladduwahetty, T.; Smith, D. F. Synlett 1991,
29e30.
dd, J¼16.8, 4.8 Hz), 1.77 (3H, s); 13C NMR (CDCl3)
d 178.4, 176.8,